Arylindenopyridines and related therapeutic and prophylactic methods

ABSTRACT

This invention provides novel arylindenopyridines of the formula:  
                 
 
     , and pharmaceutical compositions comprising same, useful for treating disorders ameliorated by reducing PDE activity in appropriate cells. This invention also provides therapeutic and prophylactic methods using the instant pharmaceutical compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. §119(e) of provisional application Serial No. 60/284,465, filed on Apr. 18, 2001 which is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] This invention relates to novel arylindenopyridines and their therapeutic and prophylactic uses. Disorders treated and/or prevented using these compounds include inflammatory and AIDS-related disorders.

BACKGROUND OF THE INVENTION

[0003] There are eleven known families of phosphodiesterases (PDE) widely distributed in many cell types and tissues. In their nomenclature, the number indicating the family is followed by a capital letter that indicates a distinct gene. A PDE inhibitor increases the concentration of cAMP in tissue cells, and hence, is useful in the prophylaxis or treatment of various diseases caused by the decrease in cAMP level which is induced by the abnormal metabolism of cAMP. These diseases include conditions such as hypersensitivity, allergy, arthritis, asthma, bee sting, animal bite, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, a urinary tract disorder, inflammatory bowel disease, stroke, erectile dysfunction, HIV/AIDS, cardiovascular disease, gastrointestinal motility disorder, and psoriasis.

[0004] Among known phosphodiesterases today, PDE1 family are activated by calcium-calmodulin; its members include PDE1A and PDE1B, which preferentially hydrolyze cGMP, and PDE1C which exhibits a high affinity for both cAMP and cGMP. PDE2 family is characterized as being specifically stimulated by cGMP. PDE2A is specifically inhibited by erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA). Enzymes in the PDE3 family (e.g. PDE3A, PDE3B) are specifically inhibited by cGMP. PDE4 (e.g. PDE4A, PDE4B, PDE4C, PDE4D) is a cAMP specific PDE present in T-cells, which is involved in inflammatory responses. A PDE3 and/or PDE4 inhibitor would be predicted to have utility in the following disorders: autoimmune disorders (e.g. arthritis), inflammatory bowel disease, bronchial disorders (e.g. asthma), HIV/AIDS, and psoriasis. A PDE5 (e.g. PDE5A) inhibitor would be useful for the treatment of the following disorders: cardiovascular disease and erectile dysfunction. The photoreceptor PDE6 (e.g. PDE6A, PDE6B, PDE6C) enzymes specifically hydrolyze cGMP. PDE8 family exhibits high affinity for hydrolysis of both cAMP and cGMP but relatively low sensitivity to enzyme inhibitors specific for other PDE families.

[0005] Phosphodiesterase 7 (PDE7A, PDE7B) is a cyclic nucleotide phosphodiesterase that is specific for cyclic adenosine monophosphate (cAMP). PDE7 catalyzes the conversion of cAMP to adenosine monophosphate (AMP) by hydrolyzing the 3′-phosphodiester bond of cAMP. By regulating this conversion, PDE7 allows for non-uniform intracellular distribution of cAMP and thus controls the activation of distinct kinase signalling pathways. PDE7A is primarily expressed in T-cells, and it has been shown that induction of PDE7A is required for T-cell activation (Li, L.; Yee, C.; Beavo, J. A. Science 1999, 283, 848). Since PDE7A activation is necessary for T-cell activation, small molecule inhibitors of PDE7 would be useful as immunosuppressants. An inhibitor of PDE7A would be predicted to have immunosuppressive effects with utility in therapeutic areas such as organ transplantation, autoimmune disorders (e.g. arthritis), HIV/AIDS, inflammatory bowel disease, asthma, allergies and psoriasis.

[0006] Few potent inhibitors of PDE7 have been reported. Most inhibitors of other phosphodiesterases have IC₅₀'s for PDE7 in the 100 μM range. Recently, Martinez, et al., (J. Med. Chem. 2000, 43, 683) reported a series of PDE7 inhibitors, among which the two best compounds have PDE7 IC₅₀'s of 8 and 13 μM. However, these compounds were only 2-3 times selective for PDE7 over PDE4 and PDE3.

[0007] Finally, the following compounds have been disclosed, and some of them are reported to show antimicrobial activity against strains such as Plasmodium falciparum, Candida albicans and Staphylococcus aureus (Gorlitzer, K.; Herbig, S.; Walter, R. D. Pharmazie 1997, 504):

SUMMARY OF THE INVENTION

[0008] This invention provides a compound having the structure of Formula I

[0009] or a pharmaceutically acceptable salt thereof, wherein

[0010] (a) R₁ is selected from the group consisting of:

[0011] (i) —COR₅, wherein R₅ is selected from H, optionally substituted C₁₋₈ straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;

[0012]  wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C₁₋₈ alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR₂₀R₂₁ wherein R₂₀ and R₂₁ are independently selected from the group consisting of hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl, benzyl, aryl, or heteroaryl or NR₂₀R₂₁ taken together form a heterocycle or heteroaryl;

[0013] (ii) COOR₆, wherein R₆ is selected from H, optionally substituted C₁₋₈ straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;

[0014]  wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C₁₋₈ alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR₂₀R₂₁ wherein R₂₀ and R₂₁ are independently selected from the group consisting of hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl, benzyl, aryl, or heteroaryl or NR₂₀R₂₁ taken together form a heterocycle or heteroaryl;

[0015] (iii) cyano;

[0016] (iv) a lactone or lactam formed with R₄;

[0017] (v) —CONR₇R₈ wherein R₇ and R₈ are independently selected from H, C₁₋₈ straight or branched chain alkyl C₃₋₇ cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl;

[0018] wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl,

[0019]  or R₇ and R₈ taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;

[0020] (b) R₂ is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C₃₋₇ cycloalkyl;

[0021] (c) R₃ is from one to four groups independently selected from the group consisting of:

[0022] (i) hydrogen, halo, C₁₋₈ straight or branched chain alkyl, arylalkyl, C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈ alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈ carboxylate, aryl, heteroaryl, and heterocyclyl;

[0023] (ii) —NR₁₀R₁₁ wherein R₁₀ and R₁₁ are independently selected from H, C₁₋₈ straight or branched chain alkyl, arylalkyl, C₃₋₇ cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R₁₀ and R₁₁ taken together with the nitrogen form a heteroaryl or heterocyclyl group;

[0024] (iii) —NR₁₂COR₁₃ wherein R₁₂ is selected from hydrogen or alkyl and R₁₃ is selected from hydrogen, alkyl, substituted alkyl, C₁₋₃alkoxyl, carboxyalkyl, R₃₀R₃₁N(CH₂)_(p)—, R₃₀R₃₁NCO(CH₂)_(p)—, aryl, arylalkyl, heteroaryl and heterocyclyl or R₁₂ and R₁₃ taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R₃₀ and R₃₁ are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6,

[0025]  wherein the alkyl group may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl;

[0026] (c) R₄ is selected from the group consisting of (i) hydrogen, (ii) C₁₋₃ straight or branched chain alkyl, (iii) benzyl and (iv) —NR₁₃R₁₄, wherein R₁₃ and R₁₄ are independently selected from hydrogen and C₁₋₆ alkyl;

[0027]  wherein the C₁₋₃alkyl and benzyl groups are optionally substituted with one or more groups selected from C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈ alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈ carboxylate, amino, NR₁₃R₁₄, aryl and heteroaryl; and

[0028] (e) X is selected from S and O;

[0029] with the proviso that when R₄ is isopropyl, then R₃ is not halogen.

[0030] In an alternative embodiment, the invention is directed to compounds of Formula I wherein R₁, R₃ and R₄ are as described above and R₂ is —NR₁₅R₁₆ wherein R₁₅ and R₁₆ are independently selected from hydrogen, optionally substituted C₁₋₈ straight or branched chain alkyl, arylalkyl, C₃₋₇ cycloalkyl, aryl, heteroaryl, and heterocyclyl or R₁₅ and R₁₆ taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R₂ is NHR₁₆, R₁ is not —COOR₆ where R₆ is ethyl.

[0031] This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.

[0032] This invention further provides a method of treating a subject having a disorder ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.

[0033] Finally, this invention provides a method of preventing a disorder ameliorated by reducing PDE activity in appropriate cells in a subject, comprising administering to the subject a prophylactically effective dose of the compound of claim 1 either preceding or subsequent to an event anticipated to cause a disorder ameliorated by reducing PDE activity in appropriate cells in the subject.

DETAILED DESCRIPTION OF THE INVENTION

[0034] Compounds of Formula I are potent small molecule phosphodiesterase inhibitors that have demonstrated potency for inhibition of PDE7, PDE5, and PDE4. Some of the compounds of this invention are potent small molecule PDE7 inhibitors which have also demonstrated good selectivity against PDE5 and PDE4.

[0035] Preferred embodiments for R₁ are COOR₆, wherein R₆ is selected from H, optionally substituted C₁₋₈ straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl. Preferably R₆ is H, or C₁₋₈ straight or branched chain alkyl which may be optionally substituted with a substituent selected from CN and hydroxy.

[0036] Preferred embodiments for R₂ are optionally substituted aryl and optionally substituted heteroaryl. Preferred substituents are from one to three members selected from the group consisting of halogen, alkyl, alkoxy, alkoxyphenyl, halo, triflouromethyl, trifluoro or difluoromethoxy, amino, alkylamino, hydroxy, cyano, and nitro. Preferably, R₂ is optionally substituted phenyl or napthyl or R₂ is

[0037] optionally substituted with from one to three members selected from the group consisting of halogen, alkyl, hydroxy, cyano, and nitro. In another embodiment of the instant compound, R₂ is —NR₁₅R₁₆.

[0038] Preferred substituents for R₃ include:

[0039] (i) hydrogen, halo, C₁₋₈ straight or branched chain alkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈ alkylsulfonyl, halogen, nitro, and hydroxy;

[0040] (ii) —NR₁₀R₁₁ wherein R₁₀ and R₁₁ are independently selected from H, C₁₋₈ straight or branched chain alkyl, arylC₁₋₈alkyl, C₃₋₇ cycloalkyl, carboxyC₁₋₈alkyl, aryl, heteroaryl, and heterocyclyl or R₁₀ and R₁₁ taken together with the nitrogen form a heteroaryl or heterocyclyl group;

[0041] (iii) —NR₁₂COR₁₃ wherein R₁₂ is selected from hydrogen or alkyl and R₁₃ is selected from hydrogen, alkyl, substituted alkyl, C₁₋₃alkoxyl, carboxyC₁₋₈alkyl, aryl, arylalkyl, R₃₀R₃₁N (CH₂)_(p)—, R₃₀R₃₁NCO(CH₂)_(p)—, heteroaryl and heterocyclyl or R₁₂ and R₁₃ taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R₃₀ and R₃₁ are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6.

[0042] Particularly, R₃ is selected from the group consisting of

[0043] Preferred embodiments for R₄ include hydrogen, C₁₋₃ straight or branched chain alkyl, particularly methyl, and amino.

[0044] In a further embodiment of the instant compound, R₁ is COOR₆ and R₂ is selected from the group consisting of substituted phenyl, and substituted naphthyl or R₂ is NR₁₅R₁₆.

[0045] More particularly, R₁ is COOR₆ where R₆ is alkyl, R₂ is substituted phenyl or naphthyl or R₂ is NR₁₅R₁₆, and R₃ is selected from the group consisting of H, nitro, amino, NHAc, halo, hydroxy, alkoxy, or a moiety of the formulae:

[0046] , alkyl(CO)NH—, and R₄ is selected from hydrogen, C₁₋₃ straight or branched chain alkyl, particularly methyl, and amino.

[0047] In a preferred embodiment, the compound is selected from the group of compounds shown in Table 1 hereinafter.

[0048] More preferably, the compound is selected from the following compounds:

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 2-amino-4-(1,3-benzodioxol-5-yl)-5-oxo-, ethyl ester

[0049]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(6-bromo-1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester

[0050]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester

[0051]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(6-bromo-1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, methyl ester

[0052]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester

[0053]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-(acetylamino)-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester

[0054]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 2-methyl-4-(3-methylphenyl)-5-oxo-, methyl ester

[0055]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester

[0056]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-2-methyl-4-(4-methyl-1-naphthalenyl)-5-oxo-, methyl ester

[0057]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-8-nitro-5-oxo-, methyl ester

[0058]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7,8-dichloro-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester

[0059]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester

[0060]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester

[0061]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-[(3-carboxy-1-oxopropyl)amino]-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester

[0062]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-[(3-carboxy-1-oxopropyl)amino]-2-methyl-4-(4-methyl-1-naphthalenyl)-5-oxo-, methyl ester

[0063]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-8-[[4-(hydroxyamino)-1,4-dioxobutyl]amino]-2-methyl-5-oxo-, methyl ester

[0064]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl)amino]acetyl]amino]-2-methyl-5-oxo-, methyl ester

[0065]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-[(4-carboxy-1-oxobutyl)amino]-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester

[0066]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl)methylamino]acetyl]amino]-2-methyl-5-oxo-, methyl ester

[0067]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-8-[(4-morpholinylacetyl)amino]-5-oxo-, methyl ester

[0068]

5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-5-oxo-8-[(1-piperazinylacetyl)amino]-, methyl ester

[0069] The instant compounds can be isolated and used as free bases. They can also be isolated and used as pharmaceutically acceptable salts. Examples of such salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, palmoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic and saccharic.

[0070] This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.

[0071] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like. The typical solid carrier is an inert substance such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. Parenteral carriers include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like. Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like. All carriers can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art.

[0072] This invention further provides a method of treating a subject having a condition ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.

[0073] In one embodiment, the disorder is an inflammatory disorder. In another embodiment, the disorder is an AIDS-related disorder. Examples of disorders treatable by the instant pharmaceutical composition include, without limitation, organ transplantation, autoimmune disorders (e.g. arthritis), immune challenge such as a bee sting, inflammatory bowel disease, bronchial disorders (e.g. asthma), HIV/AIDS, cardiovascular disorder, erectile dysfunction, allergies, and psoriasis. In the preferred embodiment, the disorder is rheumatoid arthritis.

[0074] As used herein, the term “subject” includes, without limitation, any animal or artificially modified animal having a disorder ameliorated by reducing PDE activity in appropriate cells. In a preferred embodiment, the subject is a human. In a more preferred embodiment, the subject is a human.

[0075] As used herein, “appropriate cells” include, by way of example, cells which display PDE activity. Specific examples of appropriate cells include, without limitation, T-lymphocytes, muscle cells, neuro cells, adipose tissue cells, monocytes, macrophages, fibroblasts.

[0076] Administering the instant pharmaceutical composition can be effected or performed using any of the various methods known to those skilled in the art. The instant compounds can be administered, for example, intravenously, intramuscularly, orally and subcutaneously. In the preferred embodiment, the instant pharmaceutical composition is administered orally. Additionally, administration can comprise giving the subject a plurality of dosages over a suitable period of time. Such administration regimens can be determined according to routine methods.

[0077] As used herein, a “therapeutically effective dose” of a pharmaceutical composition is an amount sufficient to stop, reverse or reduce the progression of a disorder. A “prophylactically effective dose” of a pharmaceutical composition is an amount sufficient to prevent a disorder, i.e., eliminate, ameliorate and/or delay the disorder's onset. Methods are known in the art for determining therapeutically and prophylactically effective doses for the instant pharmaceutical composition. The effective dose for administering the pharmaceutical composition to a human, for example, can be determined mathematically from the results of animal studies.

[0078] In one embodiment, the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.001 mg/kg of body weight to about 200 mg/kg of body weight of the instant pharmaceutical composition. In another embodiment, the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.05 mg/kg of body weight to about 50 mg/kg of body weight. More specifically, in one embodiment, oral doses range from about 0.05 mg/kg to about 100 mg/kg daily. In another embodiment, oral doses range from about 0.05 mg/kg to about 50 mg/kg daily, and in a further embodiment, from about 0.05 mg/kg to about 20 mg/kg daily. In yet another embodiment, infusion doses range from about 1.0 μg/kg/min to about 10 mg/kg/min of inhibitor, admixed with a pharmaceutical carrier over a period ranging from about several minutes to about several days. In a further embodiment, for topical administration, the instant compound can be combined with a pharmaceutical carrier at a drug/carrier ratio of from about 0.001 to about 0.1.

[0079] This invention still further provides a method of preventing an inflammatory response in a subject, comprising administering to the subject a prophylactically effective amount of the instant pharmaceutical composition either preceding or subsequent to an event anticipated to cause the inflammatory response in the subject. In the preferred embodiment, the event is an insect sting or an animal bite.

[0080] Definitions and Nomenclature

[0081] Unless otherwise noted, under standard nomenclature used throughout this disclosure the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.

[0082] As used herein, the following chemical terms shall have the meanings as set forth in the following paragraphs: “independently”, when in reference to chemical substituents, shall mean that when more than one substituent exists, the substituents may be the same or different;.

[0083] “Alkyl” shall mean straight, cyclic and branched-chain alkyl. Unless otherwise stated, the alkyl group will contain 1-20 carbon atoms. Unless otherwise stated, the alkyl group may be optionally substituted with one or more groups such as halogen, OH, CN, mercapto, nitro, amino, C₁-C₈-alkyl, C₁-C₈-alkoxyl, C₁-C₈-alkylthio, C₁-C₈-alkyl-amino, di(C₁-C₈-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C₁-C₈-alkyl-CO—O—, C₁-C₈-alkyl-CO—NH—, carboxamide, hydroxamic acid, sulfonamide, sulfonyl, thiol, aryl, aryl(c₁-c₈)alkyl, heterocyclyl, and heteroaryl.

[0084] “Alkoxy” shall mean —O-alkyl and unless otherwise stated, it will have 1-8 carbon atoms.

[0085] “Halogen” shall mean fluorine, chlorine, bromine or iodine; “PH” or “Ph” shall mean phenyl; “Ac” shall mean acyl; “Bn” shall mean benzyl.

[0086] The term “acyl” as used herein, whether used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group. The term “Ac” as used herein, whether used alone or as part of a substituent group, means acetyl.

[0087] “Aryl” or “Ar,” whether used alone or as part of a substituent group, is a carbocyclic aromatic radical including, but not limited to, phenyl, 1- or 2-naphthyl and the like. The carbocyclic aromatic radical may be substituted by independent replacement of 1 to 5 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C₁-C₈-alkyl, C₁-C₈-alkoxyl, C₁-C₈-alkylthio, C₁-C₈-alkyl-amino, di(C₁-C₈-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C₁-C₈-alkyl-CO—O—, C₁-C₈-alkyl-CO—NH—, or carboxamide. Illustrative aryl radicals include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. “Ph” or “PH” denotes phenyl.

[0088] Whether used alone or as part of a substituent group, “heteroaryl” refers to a cyclic, fully unsaturated radical having from five to ten ring atoms of which one ring atom is selected from S, O, and N; 0-2 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. The radical may be joined to the rest of the molecule via any of the ring atoms. Exemplary heteroaryl groups include, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, triazinyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, indolyl, isothiazolyl, 2-oxazepinyl, azepinyl, N-oxo-pyridyl, 1-dioxothienyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl-N-oxide, benzimidazolyl, benzopyranyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, indazolyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or furo[2,3-b]pyridinyl), imidazopyridinyl (such as imidazo[4,5-b]pyridinyl or imidazo[4,5-c]pyridinyl), naphthyridinyl, phthalazinyl, purinyl, pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl, thienothienyl, and furyl. The heteroaryl group may be substituted by independent replacement of 1 to 5 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C₁-C₈-alkyl, C₁-C₈-alkoxyl, C₁-C₈-alkylthio, C₁-C₈-alkyl-amino, di(C₁-C₈-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C₁-C₈-alkyl-CO—O—, C₁-C₈-alkyl-CO—NH—, or carboxamide. Heteroaryl may be substituted with a mono-oxo to give for example a 4-oxo-1H-quinoline.

[0089] The terms “heterocycle,” “heterocyclic,” and “heterocyclo” refer to an optionally substituted, fully or partially saturated cyclic group which is, for example, a 4- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. The nitrogen atoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.

[0090] Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl; pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolyl; oxazolidinyl; isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl; piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl; tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl; thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone; 1,3-dioxolane; dioxanyl; thietanyl; thiiranyl; and the like. Exemplary bicyclic heterocyclic groups include quinuclidinyl; tetrahydroisoquinolinyl; dihydroisoindolyl; dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl; dihydrobenzothiopyranyl; dihydrobenzothiopyranyl sulfone; dihydrobenzopyranyl; indolinyl; isochromanyl; isoindolinyl; piperonyl; tetrahydroquinolinyl; and the like.

[0091] Substituted aryl, substituted heteroaryl, and substituted heterocycle may also be substituted with a second substituted-aryl, a second substituted-heteroaryl, or a second substituted-heterocycle to give, for example, a 4-pyrazol-1-yl-phenyl or 4-pyridin-2-yl-phenyl.

[0092] Designated numbers of carbon atoms (e.g., C₁₋₈) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.

[0093] Unless specified otherwise, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.

[0094] Where the compounds according to this invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds possess two or more stereogenic centers, they may additionally exist as diastereomers. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

[0095] Some of the compounds of the present invention may have trans and cis isomers. In addition, where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomers. The non-racemic forms may be obtained by either synthesis or resolution. The compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation. The compounds may also be resolved by covalent linkage to a chiral auxiliary, followed by chromatographic separation and/or crystallographic separation, and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using chiral chromatography.

[0096] This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that these are only illustrative of the invention as described more fully in the claims which follow thereafter. Additionally, throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.

[0097] Experimental Details

[0098] I. General Synthetic Schemes

[0099] Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and illustrated in the following general schemes. The products of some schemes can be used as intermediates to produce more than one of the instant compounds. The choice of intermediates to be used to produce subsequent compounds of the present invention is a matter of discretion that is well within the capabilities of those skilled in the art.

[0100] Procedures described in Scheme 1, wherein R_(3a), R_(3b), R_(3c), and R_(3d) are independently any R₃ group, and R₁, R₂, R₃, and R₄ are as described above, can be used to prepare compounds of the invention wherein X is O.

[0101] Benzylidenes 2 may be obtained by known methods (Bullington, J. L; Cameron, J. C.; Davis, J. E.; Dodd, J. H.; Harris, C. A.; Henry, J. R.; Pellegrino-Gensey, J. L.; Rupert, K. C.; Siekierka, J. J. Bioorg. Med. Chem. Lett. 1998, 8, 2489; Petrow, V.; Saper, J.; Sturgeon, B. J. Chem. Soc. 1949, 2134). Hantzsch reaction of the benzylidene compounds with enamines 3 can be performed in refluxing acetic acid (Petrow et al., supra). When the desired enamines are not available, alternate Hantzsch conditions may be utilized which involve adding ammonium acetate to the reaction. The resulting dihydropyridines 4 are oxidized with chromium trioxide to obtain the desired pyridines 1 (Petrow et al., supra). In cases where the substitution pattern on the fused aromatic ring (R₃) leads to a mixture of regioisomers, the products can be separated by column chromatography.

[0102] In some cases, especially where R₂ is an alkyl group, another modification of the Hantzsch may be performed which uses three components (Bocker, R. H.; Buengerich, P. J. Med. Chem. 1986, 29, 1596). Where R₂ is an alkyl group it is also necessary to perform the oxidation with DDQ or MnO₂ instead of chromium (VI) oxide (Vanden Eynde, J. J.; Delfosse, F.; Mayence, A.; Van Haverbeke, Y. Tetrahedron 1995, 51, 6511).

[0103] In order to obtain the corresponding carboxylic acids and amides, the cyanoethyl esters 5 are prepared as described above. The esters are converted to the carboxylic acids by treatment with sodium hydroxide in acetone and water (Ogawa, T.; Matsumoto, K.; Yokoo, C.; Hatayama, K.; Kitamura, K. J. Chem. Soc., Perkin Trans. 1 1993, 525). The corresponding amides can then be obtained from the acids using standard means.

[0104] The procedure for making compounds where R₄ is NH₂ may be slightly modified. These compounds are prepared in one step from the benzylidenes 2 and alkyl amidinoacetate (Kobayashi, T.; Inoue, T.; Kita, Z.; Yoshiya, H.; Nishino, S.; Oizumi, K.; Kimura, T. Chem. Pharm. Bull. 1995, 43, 788) as depicted in Scheme 4 wherein R is R₅ or R₆ as described above.

[0105] The dihydropyridine lactones 9 can be synthesized from benzylidenes 8 (Zimmer, H.; Hillstrom, W. W.; Schmidt, J. C.; Seemuth, P. D.; Vogeli, R. J. Org. Chem. 1978, 43, 1541) and 1,3-indanedione, as shown in Scheme 5, and the corresponding pyridine is then obtained by oxidation with manganese dioxide.

[0106] Representative schemes to modify substituents on the fused aromatic ring are shown below. The amines 11 are obtained from the corresponding nitro compounds 10 by reduction with tin (II) chloride (Scheme 6). Reaction of the amines with acetyl chloride provide the amides 12.

[0107] In accordance with Scheme 7 wherein Y is O, and n is an integer from 1-3, an alkyl chain with a carboxylic acid at the terminal end can also be added to the amines 11. For example, reaction with either succinic anhydride (Omuaru, V. O. T.; Indian J. Chem., Sect B. 1998, 37, 814) or β-propiolactone (Bradley, G.; Clark, J.; Kernick, W. J. Chem. Soc., Perkin Trans. 1 1972, 2019) can provide the corresponding carboxylic acids 13. These carboxylic acids are then converted to the hydroxamic acids 14 by treatment with ethyl chloroformate and hydroxylamine (Reddy, A. S.; Kumar, M. S.; Reddy, G. R. Tetrahedron Lett 2000, 41, 6285).

[0108] The amines 11 can also be treated with glycolic acid to afford alcohols 15 (Jursic, B. S.; Zdravkovski, Z. Synthetic Comm. 1993, 23, 2761) as shown in Scheme 8.

[0109] As shown in Scheme 9, the aminoindenopyridines 11 may also be treated with chloroacetylchloride followed by amines to provide the more elaborate amines 16 (Weissman, S. A.; Lewis, S.; Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1998, 39, 7459). Where R₆ is a hydroxyethyl group, the compounds can be further converted to piperazinones 17.

[0110] The 4-aminoindenopyridines 18 can be synthesized from the 4-chloroindenopyridines 19 using a known procedure (Gorlitzer, K.; Herbig, S.; Walter, R. D. Pharmazie 1997, 504) or via palladium catalyzed coupling (Scheme 10).

[0111] II. Specific Compound Syntheses

[0112] Specific compounds which are representative of this invention can be prepared as per the following examples. No attempt has been made to optimize the yields obtained in these reactions. Based on the following, however, one skilled in the art would know how to increase yields through routine variations in reaction times, temperatures, solvents and/or reagents.

[0113] The products of certain syntheses can be used as intermediates to produce more than one of the instant compounds. In those cases, the choice of intermediates to be used to produce compounds of the present invention is a matter of discretion that is well within the capabilities of those skilled in the art.

EXAMPLE 1 Hantzsch Condensation to Form Dihydropyridine 4 (R₁=COOMe; R₂=3,5-dimethylphenyl; R_(3b,c)=Cl; R_(3a,b)=H; R₄=Me)

[0114] To a refluxing solution of benzylidene 2 (0.500 g, 1.5 mmol) in acetic acid (10 mL) was added methyl-3-aminocrotonate (0.695 g, 6.0 mmol). The reaction was heated to reflux for 20 minutes, then water was added until a precipitate started to form. The reaction was cooled to room temperature. The mixture was filtered and washed with water to obtain 0.354 g (55%) of a red solid. MS m/z 450 (M⁺+23), 428 (M⁺+1).

EXAMPLE 2 Alternate Hantzsch Conditions to Form Dihydropyridine 4 (R₁=CO₂Me; R₂=2,4-dimethylphenyl; R₃=H; R₄=Et)

[0115] To a refluxing solution of benzylidene 2 (1.00 g, 3.82 mmol) in acetic acid (12 Ml) was added methyl propionylacetate (1.98 g, 15.2 mmol) and ammonium acetate (1.17 g, 15.2 mmol). The reaction was heated for 20 min and then cooled to room temperature. No product precipitated from the solution, so the reaction was heated to reflux and then water was added until a solid began to precipitate. After cooling to room temperature, the mixture was filtered and the red solid washed with water to yield 1.29 g (90%) of product. MS m/z 396 (M⁺+23), 374 (M⁺+1).

EXAMPLE 3 Oxidation of Dihydropyridine 4 to Pyridine 1 (R₁=COOMe, R₂=3,5-dimethylphenyl; R_(3b,c)=Cl; R_(3a,d)=H; R₄=Me)

[0116] To a refluxing solution of dihydropyridine 4 (0.250 g, 0.58 mmol) in acetic acid (10 mL) was added a solution of chromium (VI) oxide (0.584 g, 0.58 mmol) in 1 mL water. After 30 minutes at reflux, the reaction was diluted with water until a precipitate started to form. The mixture was cooled to room temperature and allowed to stand overnight. The mixture was filtered and washed with water to give 0.199 g (81%) of a yellow solid. MS m/z 448 (M⁺+23), 426 (M⁺+1).

EXAMPLE 4 Oxidation of Dihydropyridine 4 to Pyridine 1 (R₁=COOMe; R₂=(4-methyl)-1-naphthyl; R_(3b,c)=H, NO₂/NO₂, H; R=Me)

[0117] To a refluxing suspension of regioisomeric dihydropyridines 4 (3.59 g, 8.16 mmol) in acetic acid (40 mL) was added a solution of chromium (VI) oxide (0.816 g, 8.16 mmol) in 3 mL water. After 20 minutes at reflux, the reaction was diluted with water until a precipitate started to form. The mixture was cooled to room temperature and allowed to stand overnight. The mixture was filtered and washed with water to yield the mixture of regioisomers as a yellow solid. The products were purified by column chromatography eluting with hexanes:ethyl acetate to yield 1.303 g (37%) of pyridine 1 (R_(3b)=NO₂; R_(3c)=H) and 0.765 g (21%) of its regioisomer (R_(3b)=H: R_(3c)=NO₂). MS m/z 461 (M⁺+23), 439 (M⁺+1).

EXAMPLE 5 Alternate Three Component Hantzsch Reaction to Form Dihydropyridine 4 (R₁=CO₂Me; R₂=cyclohexyl; R₃=H; R₄=Me)

[0118] Cyclohexane carboxaldehyde (2.0 g, 17.8 mmol), 1,3-indandione (2.6 g, 17.8 mmol), methylacetoacetate (2.0 g, 17.8 mmol), and ammonium hydroxide (1 mL) were refluxed in 8 mL of methanol for 1.5 hours. The temperature was lowered to approximately 50° C. and the reaction was stirred overnight. The reaction was cooled to room temperature, filtered and the solid washed with water. The residue was then dissolved in hot ethanol and filtered while hot. The filtrate was concentrated to yield 4.1 g (68%) of the product which was used without purification. MS m/z 336 (M⁻−1).

EXAMPLE 6 DDQ Oxidation of Dihydropyridine 4 (R₁=CO₂Me; R₂=cyclohexyl; R₃=H; R₄=Me)

[0119] To a solution of dihydropyridine 4 (2.50 g, 7.40 mmol) in 15 mL of dichloromethane was added 2,3-dichloro-3,6-dicyano-1,4-benzoquinone (1.70 g, 7.40 mmol). The reaction was stirred at room temperature for four hours. The mixture was filtered and the residue was washed with dichloromethane. After the filtrate was concentrated, the residue was purified by column chromatography eluting with ethyl acetate: hexanes to yield 0.565 g (23%) of a yellow solid. MS m/z 358 (M⁺+23), 336 (M⁺+1).

EXAMPLE 7 MnO₂ Oxidation of Dihydropyridine 4 (R₁=CO₂Me; R₂=4-(dimethylamino)phenyl; R₃=H; R₄=Me)

[0120] To a solution of dihydropyridine 4 (0.50 g, 1.3 mmol) in 10 mL of dichloromethane was added manganese dioxide (2.5 g, 28.7 mmol). The reaction was stirred at room temperature overnight before filtering and washing with dichloromethane. The filtrate was concentrated to yield 0.43 g (88%) of orange solid 1. MS m/z 395 (M⁺+23), 373 (M⁺+1).

EXAMPLE 8 Cleavage of Carboxylic Ester 5 (R₂=2,4-dimethylphenyl; R₃=H; R₄=Me)

[0121] To a suspension of ester 5 (2.75 g, 6.94 mmol) in acetone (50 mL) was added aqueous 1 M NaOH (100 mL). After stirring at room temperature for 24 hours, the reaction mixture was diluted with 100 mL of water and washed with dichloromethane (2×100 mL). The aqueous layer was cooled to 0° C. and acidified with concentrated HCl. The mixture was filtered and washed with water to yield 1.84 g (77%) yellow solid 6. MS m/z 366 (M⁺+23), 343 (M⁺+1).

EXAMPLE 9 Preparation of Amide 7 (R₂=2,4-dimethylphenyl; R₃=H; R₄=Me; R₅=H; R₆=Me)

[0122] A solution of carboxylic acid 6 (0.337 g, 0.98 mmol) in thionyl chloride (10 mL) was heated at reflux for 1 hour. The solution was cooled and concentrated in vacuo. The residue was diluted with CCl₄ and concentrated to remove the residual thionyl chloride. The residue was then dissolved in THF (3.5 mL) and added to a 0° C. solution of methylamine (1.47 mL of 2.0 M solution in THF, 2.94 mmol) in 6.5 mL THF. The reaction was warmed to room temperature and stirred overnight. The mixture was poured into water, filtered, washed with water and dried to yield 0.263 g (75%) of tan solid. MS m/z 357 (M⁺+1).

EXAMPLE 10 Preparation of Pyridine 1 (R₁=CO₂Et; R₂=4-nitrophenyl; R₃=H; R₄=NH₂)

[0123] To a refluxing solution of benzylidene 2 (1.05 g, 3.76 mmol) in 10 mL of acetic acid was added ethyl amidinoacetate acetic acid salt (0.720 g, 3.76 mmol). The resulting solution was heated at reflux overnight. After cooling to room temperature, the resulting precipitate was removed by filtration and washed with water. This impure residue was heated in a minimal amount of ethanol and then filtered to yield 0.527 g (35%) of a yellow solid. MS m/z 412 (M⁺+23), 390 (M⁺+1).

EXAMPLE 11 Hantzsch Condensation of Benzylidene 8 (R₂=3-methoxyphenyl) and 1,3-indandione)

[0124] The benzylidene 8 (2.00 g, 9.2 mmol), 1,3-indandione (1.34 g, 0.2 mmol) and ammonium acetate (2.83 g, 36.7 mmol) were added to 30 mL of ethanol and heated to reflux overnight. The reaction mixture was cooled to room temperature and diluted with ethanol. A yellow precipitate was collected by filtration, washed with ethanol, and dried under vacuum to yield 1.98 g (63%) of the dihydropyridine 9. MS m/z 346 (M⁺+1).

EXAMPLE 12 Reduction to Prepare Amine 11 (R₁=CO₂Me; R₂=4-methylnaphthyl; R₄=Me)

[0125] To a refluxing suspension of pyridine 10 (0.862 g, 1.97 mmol) in 35 mL of ethanol was added a solution of tin (II) chloride dihydrate (1.33 g, 5.90 mmol) in 6 mL of 1:1 ethanol: concentrated HCl. The resulting solution was heated at reflux overnight. Water was added until a precipitate started to form and the reaction was cooled to room temperature. The mixture was then filtered and washed with water. After drying, the residue was purified by column chromatography eluting with hexanes: ethyl acetate to yield 0.551 g (69%) of an orange solid. MS m/z 431 (M⁺+23), 409 (M⁺+1).

EXAMPLE 13 Acetylation of Amine 11 (R₁=CO₂Et; R₂=3,4-methylenedioxyphenyl; R₄=Me)

[0126] To a solution of amine 11 (0.070 g, 0.174 mmol) in 15 mL of dichloromethane was added triethylamine (0.026 g, 0.261 mmol) and acetyl chloride (0.015 g, 0.192 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with water and then extracted with dichloromethane (3×35 mL). The combined organics were washed with brine, dried over MgSO₄, and concentrated. The residue was purified by silica gel chromatography eluting with hexanes: ethyl acetate to yield 0.054 g (70%) of amide 12. MS m/z 467 (M⁺+23), 445 (M⁺+1).

EXAMPLE 14 Preparation of Carboxylic Acid 13 (R₁=CO₂Me; R₂=3,5-dimethylphenyl; R₄=Me; Y=O; n=2)

[0127] To a suspension of amine 11 (0.079 g, 0.212 mmol) in 5 mL of benzene was added succinic anhydride (0.021 g, 0.212 mmol). After heating at reflux for 24 hours, the reaction mixture was filtered and washed with benzene. The residue was dried under high vacuum and then washed with ether to remove the excess succinic anhydride. This yielded 0.063 g (63%) of carboxylic acid 13. MS m/z 473 (M⁺+1).

EXAMPLE 15 Preparation of Carboxylic Acid 13 (R₁=CO₂Me; R₂=3,5-dimethylphenyl; R₄=Me; Y=H₂; n=1)

[0128] To a refluxing solution of amine 11 (0.078 g, 0.210 mmol) in 5 mL of acetonitrile was added β-propiolactone (0.015 g, 0.210 mmol). The reaction was heated to reflux for 72 hours before cooling to room temperature. The reaction mixture was concentrated. The residue was mixed with 10% aqueous sodium hydroxide and washed sequentially with ether and ethyl acetate. The aqueous layer was acidified with concentrated HCl and extracted with dichloromethane (2×25 mL). The combined organics were dried over MgSO₄, filtered, and concentrated. The residue was purified by column chromatography eluting with 5% MeOH in dichloromethane to yield 0.020 g (21%) of an orange solid. MS m/z 467 (M⁺+23), 445 (M⁺+1).

EXAMPLE 16 Preparation of Hydroxamic Acid 14 (R₁=CO₂Me; R₂=(4-methyl)-1-naphthyl; Y=O; n=2; R₄=Me)

[0129] To a 0° C. suspension of carboxylic acid 13 (0.054 g, 0.106 mmol) in 10 mL of diethyl ether was added triethylamine (0.014 g, 0.138 mmol) and then ethyl chloroformate (0.014 g, 0.127 mmol). The mixture was stirred at 0° C. for 30 minutes and them warmed to room temperature. A solution of hydroxylamine (0.159 mmol) in methanol was added and the reaction was stirred overnight at room temperature. The mixture was filtered and the residue was washed with ether and dried under vacuum to yield 0.030 g (54%) of a yellow solid. MS m/z 524 (M⁺+1).

EXAMPLE 17 Preparation of Amide 15 (R₁=CO₂Me; R₂=3,5-dimethylphenyl; R₄=Me)

[0130] A mixture of amine 11 (0.201 g, 0.54 mmol) and glycolic acid (0.049 g, 0.65 mmol) was heated at 120-160° C. for 30 minutes. During heating, more glycolic acid was added to ensure that excess reagent was present. Once the starting material was consumed, the reaction was cooled to room temperature, and diluted with dichloromethane. The resulting mixture was extracted with 20% NaOH, followed by 10% HCl, and finally water. The combined organics were concentrated and triturated with ether. Purification by column chromatography eluting with ethyl acetate: hexanes yielded 0.012 g (5%) of a yellow solid. MS m/z 453 (M⁺+23), 431 (M⁺+1).

EXAMPLE 18 Preparation of Amide 16 (R₁=CO₂Me; R₂=3,5-dimethylphenyl; R₄=Me; NR₆R₇=morpholino)

[0131] To a 0° C. mixture of amine 11 (0.123 g, 0.331 mmol) in 2 mL of 20% aqueous NaHCO₃ and 3 mL of ethyl acetate was added chloroacetyl chloride (0.047 g, 0.413 mmol). The reaction was warmed to room temperature and stirred for 45 minutes. The mixture was poured into a separatory funnel and the aqueous layer was removed. The organic layer containing the crude chloroamide was used without purification. To the ethyl acetate solution was added morpholine (0.086 g, 0.992 mmol) and the reaction was heated to approx. 65° C. overnight. The reaction was diluted with water and cooled to room temperature. After extraction with ethyl acetate (3×25 mL), the combined organics were washed with brine, dried over MgSO₄ and concentrated to yield 0.130 g (79%) of a yellow solid. MS m/z 522 (M⁺+23), 500 (M⁺+1).

EXAMPLE 19 Preparation of Piperazinone 17 (R₁=CO₂Me; R₂=3,5-dimethylphenyl; R₄=Me; R₇=H)

[0132] To a 0° C. solution of amide 16 (R₆=CH₂CH₂OH) (0.093 g, 0.20 mmol), tri n-butylphosphine (0.055 g, 0.27 mmol) in 0.35 mL ethyl acetate was slowly added di-tert-butyl azodicarboxylate (0.062 g, 0.27 mmol) in 0.20 mL ethyl acetate. The reaction was allowed to stand for 15 minutes and then heated to 40° C. overnight. 4.2 M ethanolic HCl was added dropwise. The mixture was cooled to 0° C. and allowed to stand for 2 hours. The mixture was filtered and washed with cold ethyl acetate. Purification by column chromatography with 1-5% MeOH in CH₂Cl₂ yielded 0.011 (12%) of a white solid. MS m/z 478 (M⁺+23), 456 (M⁺+1).

EXAMPLE 20 Preparation of 4-Aminoindenopyridine 19 (R₁=CO₂Me; R₄=Me; R₆=Me; R₇=phenyl)

[0133] To a solution of 4-chloroindenopyridine 18 (0.069 g, 0.240 mmol) in 10 mL of 2-ethoxyethanol was added N-methylaniline (0.026 g, 0.240 mmol). The reaction was heated at reflux for 96 hours. After cooling to room temperature, the solution was concentrated. The residue was purified by column chromatography eluting with hexanes: ethyl acetate to yield 0.029 g (34%) of an orange solid. MS m/z 359 (M⁺+1).

EXAMPLE 21 Preparation of 4-Aminoindenopyridine 19 (R₁=CO₂Me; R₄=Me; R₆=H; R₇=cyclopentyl) by Palladium Catalyzed Coupling

[0134] A mixture of 4-chloroindenopyridine 18 (0.100 g, 0.347 mmol), cyclopentylamine (0.035 g, 0.416 mmol), palladium (II) acetate (0.004 g, 0.0017 mmol), 2-(di-t-butylphosphino)biphenyl (0.010 g, 0.0035 mmol), and cesium carbonate (0.124 g, 0.382 mmol) in 10 mL of dioxane was heated at reflux overnight. The reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×35 mL). The combined organics were washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography eluting with ethyl acetate: hexanes. The purified oil was dissolved in ether and cooled to 0° C. To this solution was slowly added 1.0 M HCl in ether. The resulting precipitate was isolated by filtration, washed with ether, and dried under vacuum to yield 0.032 g (25%) of a yellow solid. MS m/z 359 (M⁺+23), 337 (M⁺+1).

[0135] Following the general synthetic procedures outlined above and in Examples 1-21, the compounds of Table 1 below were prepared. TABLE 1 Ia

MS No. R₁ R₂ R_(3a) R_(3b) R_(3c) R_(3d) R₄ (M + 1) 1 CN

H H H H Me 341 2 CO₂Et

H H H H Me 388 3 CO₂t-Bu

H H H H Me 416 4 CO₂t-Bu

H H H H Me 432 5 CO₂Et

H H H H Me 389 6 CO₂H

H H H H Me 360 7 CO₂Et

H H H H Me 480 8 CO₂Et

H H H H Me 482 9 CO₂Et

H H H H Me 424 10 CO₂H

H H H H Me 376 11 CO₂Et Ph H H H H Me 344 12 CO₂Et

H H H H Me 374 13 CO₂Et

H H H H Me 434 14 CO₂Et

H H H H Me 454 15 CO₂Bn

H H H H Me 450 16

H H H H Me 507 17 CO₂Me

H H H H Me 390 18 CO₂Me

H H H H Me 374 19 CO₂Et

H H H H Me 404 20 CO₂Et

H H H H Me 404 21 CO₂Et

H H H H Me 454 22 CO₂Et

H H H H NH₂ 411 (M + 23) 23 CO₂Et

H H H H Me 388 25 CO₂Et

H H H H NH₂ 405 26 CO₂Et

H H H H NH₂ 390 27 CO₂Et Ph H H H H NH₂ 345 28 CO₂Et

H H H H Me 402 29 CO₂Et

H H H H Me 483 30 CO₂Me Ph H H H H Me 330 31 CO₂Et

H H H H Me 402 32 CO₂Et

H NO₂ H H Me 433 33

H H H H Me 413 34 CO₂Et

H H H H Me 433 35 CO₂Et

H H NO₂ H Me 433 36 CO₂Me

H H H H Me 398 37 CO₂Et

H H NH₂ H Me 403 38 CONH₂

H H H H Me 359 39 CO₂Et

H H H H Me 372 40 CO₂Et

H NH₂ H H Me 403 41 CO₂Et

H H H H Me 334 42 CO₂Et 2-Thienyl H H H H Me 350 43 CO₂Me

H H H H Me 358 44 CO₂Me

H H H H Me 388 45 CO₂Me

H H H H Me 419 46 CO₂Me

H H H H Me 388 47 CO₂Me 4-Pyridyl H H H H Me 331 48 CO₂Me

H H H H Me 374 49 CO₂Me

H H H H Me 454 50 CO₂Me

H H H H Me 439 51 CO₂Me

H H H H Me 358 52 CO₂Et

H H H H Me 372 53 CO₂Me

H H H H Me 410 54 CO₂Me

H H H H Me 375 55 CO₂Et

H NHAc H H Me 445 56 CO₂Et

H H NHAc H Me 445 57 CO₂Et

H H H H Me 358 58 CO₂Et

H H H H Me 358 59 CO₂Et

H H H H Me 358 60 CO₂Et

H NO₂ H H Me 457 61 CO₂Et

H H NO₂ H Me 457 62 CO₂Me

H H H H Me 344 63 CO₂Et

H NH₂ H H Me 427 64 CO₂Et

H H NH₂ H Me 427 65 CO₂Me

H H H H Me 466 66 CO₂Me

H H H H Me 344 67 CO₂Me

H H H H Me 344 68 CO₂Me

H NO₂ H H Me 443 69 CO₂Me

H H NO₂ H Me 443 70 CO₂Et

H H H H i-Pr 400 71 CO₂Me

H NH₂ H H Me 413 72 CO₂Me

H H H H Me 399 73 CO₂Me

H H H H Et 372 74 CO₂Me

H H H H Me 398 75 CO₂Me

H H H H Me 394 76 CO₂Me

H H H H Me 372 77 CO₂Me

H NO₂ H H Me 403 78 CO₂Me

H H NO₂ H Me 403 79 CO₂Me

H H H H Me 394 80 CO₂Me

H NHAc H H Me 455 81 CO₂Me

H H H H Me 488 82 CO₂Me

H NH₂ H H Me 373 83 CO₂Me

H H NH₂ H Me 373 84 CO₂Me

H H H H Me 362 85 CO₂Me

H H H H Me 431 (M + 23) 86 CO₂Me

H H H H Me 380 (M + 23) 87 CO₂Me

H NO₂ H H Me 439 88 CO₂Me

H H NO₂ H Me 439 89 CO₂Me

H H H H Me 430 90 CO₂Me

H NH₂ H H Me 409 91 CO₂Me

H H NH₂ H Me 409 92

H H H H Me 397 93 CN

H H H H Me 325 94 CO₂Me

H H H H NH₂ 359 95 CO₂Me

H H H H NH₂ 395 96 CO₂H

H H H H Me 344 97

H H H H Me 433 98 CN

H H H H Me 361 99

H H H H C₂H₂O₂ 358 100

H H H H C₂H₂O₂ 357 101

Ph H H H H C₂H₂O₂ 314 102

H H H H C₂H₂O₂ 361 103

H H H H C₂H₂O₂ 364 104

H H H H C₂H₂O₂ 342 105 CO₂H

H H H H Me 380 106 CONH₂

H H H H Me 343 107 CONHMe

H H H H Me 357 108 CONMe₂

H H H H Me 371 109

H H H H C₂H₂O₂ 378 110

H H H H C₂H₂O₂ 328 111

H H H H C₂H₂O₂ 356 112

H H H H C₂H₂O₂ 328 113 CO₂Me

H H H H Me 375 114

H H H H C₂H₂O₂ 328 115 CO₂Me

H H H H Me 373 116 CONH₂

H H H H Me 379 117

H H H H C₂H₂O₂ 365 118 CO₂Me

H H H H Me 375 119 CONHMe

H H H H Me 393 120 CONMe₂

H H H H Me 407 121 CO₂Me

H H H H Me 381 122 CO₂Me

H Cl Cl H Me 463 123 CO₂Me

H Cl Cl H Me 427 124 CO₂Me

H H H H Me 381 125 CO₂Et

H H H H Me 408 126 CO₂Me

H Cl Cl H Me 555 127 CO₂Me

Cl H H Cl Me 427 128 CO₂Me

H H H H Me 421 129 CO₂Me

Cl H H Cl Me 558 130 CO₂Me

H H H H Me 345 131 CO₂Et

H Cl Cl H Me 477 132 CO₂Me

H H H H Me 503 133 Ac

H H H H Me 472 134 Ac

H H H H Me 342 135 CO₂Me

H H H H Me 331 136

H H H H Me 527 137

H H H H Me 397 138 CO₂Me

H H H H Me 362 139 CO₂H

H H H H Me 474 140 CO₂H

H H H H Me 344 141 CO₂Me

H H H H Me 346 142 CO₂Me

H H H H Me 380 143 CO₂Me

H H H H Me 486 144 CO₂Me

H H H H Me 436 145 CO₂Me

H H H H Me 518 146

H H H H Me 557 147

H Cl Cl H Me 466 148 CO₂Et —NHPh H H H H Me 359 149 CO₂Me

H H H H Me 360 150 CO₂Me

H H H H Me 504 151

H H H H Me 420 152 C₃H₅O₃

H H H H Me 534 153

H H H H Me 385 154

H H H H Me 373 155

H H NO₂ H Me 574 156 CO₂Me

H Br H H Me 473 157 CO₂Me

H H Br H Me 473 158

H Cl Cl H Me 489 159

H H NO₂ H Me 590 160

H H H H Me 411 161 CO₂Me

H Br H H Me 436 162 CO₂Me

H H Br H Me 438 163 CO₂Me

H Br Br H Me 516 164

H Cl Cl H Me 597 165

H Cl Cl H Me 480 166 CO₂Me

H Br Br H Me 552 167 CO₂Et

H Br Br H Me 530 168 CO₂Me

F H H F Me 540 169 CO₂Me

H H NO₂ H Me 551 170 CO₂Me

H Cl Cl H Me 573 171

H H NO₂ H Me 444 172

H NO₂ H H Me 444 173 CO₂Me

F H H F Me 394 174

F H H F Me 433 175 CO₂Me

H Br Br H Me 548 176 CO₂Me

H H H H Me 355 177 CO₂Me

H NO₂ H H Me 421 178 CO₂Me

H H NO₂ H Me 453 (M + 23) 179 CO₂Me

H Cl Cl H Me 443 180 CN

H H H H Me 341 181 CO₂Me

H H H H Me 598 182 CO₂Me

H Cl Cl H Me 435 183 CO₂Et

H H H H Me 387 184 CO₂Et

H H H H Me 373 185 CO₂Me

H H H H Me 612 186 CO₂Et

H H H H Me 410 187 CO₂Me

H H NO₂ H Me 345 188 CO₂Me

H Cl Cl H Me 668 189 CO₂Me

H H NO₂ H Me 413 190 CO₂H

H Cl Cl H Me 544 191 CN

H H H H Me 565 192 CO₂Me

H Br H H Me 606 (M + 23) 193 CO₂Me

H H Br H Me 584 194 CO₂Et

H H H H Me 373 195 CO₂Et

H H H H Me 427 196 CO₂Et

H Cl Cl H Me 587 197 CO₂Et

H H H H Me 437 198 CO₂Et

H H H H Me 389 199 CO₂Et

H H H H Me 612 200 CO₂Et

H Cl Cl H Me 449 201 CO₂Me

H Cl Cl H Me 450 202 CO₂Me

H Cl Cl H Me 465 203 CO₂Me

H H H H Me 396 204 CO₂Me

H

H H Me 473 205 CO₂Me

H H H H Me 345 206 CO₂Me

H H H H Me 359 207 CO₂Me

H Cl Cl H Me 444 208 CO₂Me

H H H H Me 355 209 CO₂H

H H H H Me 366 210 CO₂Me

H Cl Cl H Me 444 211 CO₂Me

H Cl Cl H Me 430 212 CO₂Me

H H H H Me 416 213 CO₂Me

H Cl Cl H Me 430 214 CO₂Me

H H H H Me 413 215 CO₂Me

H OMe OMe H Me 418 216 CO₂Me

H OMe OMe H Me 454 217 CO₂Me

H H H H Me 362 218 CO₂Me

H

H H Me 445 219 CO₂Me

H H H H Me 359 220 CO₂Me —NHPh H H H H Me 345 221 CO₂Me

H H H H Me 423 222 CO₂Me 2-Pyridyl H H H H Me 353 (M + 23) 223 CO₂Me

H OMe OMe H Me 459 224 CO₂Me

H Cl Cl H Me 485 225 CO₂Me

H H H H Me 345 226 CO₂Me

H H NO₂ H Me 420 227 CO₂Me

H H NO₂ H Me 420 228 CO₂Me

H H H H Me 359 229 CO₂Me

H H H H Me 396 230 CO₂Me

H OH OH H Me 426 231 CO₂Me

H H F H Me 376 232 CO₂Me

H H NO₂ H Me 461 233 CO₂Me

H Cl Cl H Me 468 234 CO₂Me

H H H H Me 373 235 CO₂Me

H H H H Me 375 236 CO₂Me

H NO₂ H H Me 443 237 CO₂Me

H H NO₂ H Me 443 238 CO₂Me

H H H H Me 398 239 CO₂Me

H Cl Cl H Me 491 240 CO₂Me

H

H H Me 509 241 CO₂Me

H H

H Me 473 242 CO₂Me

H H

H Me 509 243 CO₂Me

H H H H Me 310 244 CO₂Me

H

H H Me 524 245 CO₂Me

H H

H Me 488 246 CO₂Me

H H H H Me 308 247 CO₂Me i-Pr H H H H Me 296 248 CO₂Me

H H H H Me 336 249 CO₂Me Me H H H H Me 268 250 CO₂Me

H H

H Me 474 251 CO₂Me

H H

H Me 487 252 CO₂Me N-Morpholino H H H H Me 339 253 CO₂Me

H H H H Me 337 254 CO₂Me

H H

H Me 488 255 CO₂Me

H

H H Me 474 256 CO₂Me

H

H H Me 456 257 CO₂Me

H

H H Me 431 258 CO₂Me

H

H H Me 500 259 CO₂Me

H

H H Me 499 260 CO₂Me

H

H H Me 481 261 CO₂Me

H H

H Me 500 262 CO₂Me

H H

H Me 499 263 CO₂Me

H H

H Me 431

[0136] III. Biological Assays and Activity

[0137] The assay of phosphodiesterase activity follows the homogeneous SPA (scintillation proximity assay) format under the principle that linear nucleotides preferentially bind yttrium silicate beads in the presence of zinc sulfate.

[0138] In this assay, the enzyme converts radioactively tagged cyclic nucleotides (reaction substrate) to linear nucleotides (reaction product) which are selectively captured via ion chelation on a scintillant-containing bead. Radiolabeled product bound to the bead surface results in energy transfer to the bead scintillant and generation of a quantifiable signal. Unbound radiolabel fails to achieve close proximity to the scintillant and therefore does not generate any signal.

[0139] Specifically, enzyme was diluted in PDE buffer (50 mM pH 7.4 Tris, 8.3 mM MgCl₂, 1.7 mM EGTA) with 0.1% ovalbumin such that the final signal:noise (enzyme:no enzyme) ratio is 5-10. Substrate (2,8-³H-cAMP or 8-³H-cGMP, purchased from Amersham Pharmacia) was diluted in PDE (4, 5, 7A) buffer to 1 nCi per μl (or 1 μCi/ml). For each test well, 48 μl of enzyme was mixed with 47 μl substrate and 5 μl test compound (or DMSO) in a white Packard plate, followed by shaking to mix and incubation for 15 minutes at room temperature. A 50 μl aliquot of evenly suspended yttrium silicate SPA beads in zinc sulfate was added to each well to terminate the reaction and capture the product. The plate was sealed using Topseal-S (Packard) sheets, and the beads were allowed to settle by gravity for 15-20 minutes prior to counting on a Packard TopCount scintillation counter using a ³H glass program with color quench correction. Output was in color quench-corrected dpm.

[0140] Test compounds were diluted in 100% DMSO to a concentration 20× final assay concentration. DMSO vehicle alone was added to uninhibited control wells. Inhibition (%) was calculated as follows:

Nonspecific binding (NSB)=the mean of CPM of the substrate+buffer+DMSO wells

Total Binding (TB)=the mean of the enzyme+substrate+DMSO wells ${\% \quad {Inhibition}\quad {listed}\quad {in}\quad {Table}\quad 1} = {\left( {1 - \left( \frac{{{Sample}\quad {CPM}} - {NSB}}{{TB}\text{-}{NSB}} \right)} \right) \times 100}$

[0141] The IC₅₀ values were calculated using the Deltagraph 4-parameter curve-fitting program. The IC₅₀ and % Inhibition data on PDE 4, 5, and 7A are listed for the indicated compounds in Table 2 below. TABLE 2 Ia

MS IC₅₀ (μM)/% inh. @ μM No. R₁ R₂ R_(3a) R_(3b) R_(3c) R_(3d) R₄ (M + 1) PDE7A PDE4 PDE5 6 CO₂H

H H H H Me 360 45% @20 49% @5 51 CO₂Me

H H H H Me 358 0.055 0.353 2.7 56 CO₂Et

H H NHAc H Me 445 0.074 0.333 2.5 70 CO₂Et

H H H H i-Pr 400 2.11 73 CO₂Me

H H H H Et 372 1.54 0.998 82 CO₂Me

H NH₂ H H Me 373 0.021 0.204 1.11, 0.864 90 CO₂Me

H NH₂ H H Me 409 0.005 0.237, 0.172 2.33 98 CN

H H H H Me 361 1.13 119 CONHMe

H H H H Me 393 0.658 41% @20 133 Ac

H H H H Me 472 1.54 134 Ac

H H H H Me 342 1.14 169 CO₂Me

H H NO₂ H Me 551 0.0053 0.184 170 CO₂Me

H Cl Cl H Me 573 0.0087 0.557 190 CO₂H

H Cl Cl H Me 544 5.9 191 CN

H H H H Me 565 0.593 197 CO₂Et

H H H H Me 437 0.728 69% @5 0.362 219 CO₂Me

H H H H Me 359 0.964 61% @5 1.1 220 CO₂Me —NHPh H H H H Me 345 0.084 1.8 0.637 241 CO₂Me

H H

H Me 473 0.0035 0.954 0.183 242 CO₂Me

H H

H Me 509 0.0038 0.782 0.141 243 CO₂Me

H H H H Me 310 2.6 245 CO₂Me

H H

H Me 488 0.0053 0.875 0.185 248 CO₂Me

H H H H Me 336 0.783 0.171 0.649 250 CO₂Me

H H

H Me 474 0.0074 0.684 2.4 251 CO₂Me

H H

H Me 487 0.0054 0.754 0.26 253 CO₂Me

H H H H Me 337 0.905 0.85 0.303 254 CO₂Me

H H

H Me 488 0.0067 0.664 0.765 261 CO₂Me

H H

H Me 500 0.0063 0.477 0.63 262 CO₂Me

H H

H Me 499 0.008 0.702 3.7 

What is claimed is:
 1. A compound having the structure

wherein (a) R₁ is selected from the group consisting of: (i) —COR₅, wherein R₅ is selected from H, optionally substituted C₁₋₈ straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C₁₋₈ alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR₂₀R₂₁ wherein R₂₀ and R₂₁ are independently selected from the group consisting of hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl, benzyl, aryl, or heteroaryl or NR₂₀R₂₁ taken together form a heterocycle or heteroaryl; (ii) COOR₆, wherein R₆ is selected from H, optionally substituted C₁₋₈ straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C₁₋₈ alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR₂₀R₂₁ wherein R₂₀ and R₂₁ are independently selected from the group consisting of hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl, benzyl, aryl, or heteroaryl or NR₂₀R₂₁ taken together form a heterocycle or heteroaryl; (iii) cyano; (iv) a lactone or lactam formed with R₄; (v) —CONR₇R₈ wherein R₇ and R₈ are independently selected from H, C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl,  or R₇ and R₈ taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group; (b) R₂ is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C₃₋₇ cycloalkyl; (c) R₃ is from one to four groups independently selected from the group consisting of: (i) hydrogen, halo, C₁₋₈ straight or branched chain alkyl, arylalkyl, C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈ alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈ carboxylate, aryl, heteroaryl, and heterocyclyl; (ii) —NR₁₀R₁₁ wherein R₁₀ and R₁₁ are independently selected from H, C₁₋₈ straight or branched chain alkyl, arylalkyl, C₃₋₇ cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R₁₀ and R₁₁ taken together with the nitrogen form a heteroaryl or heterocyclyl group; (iii) —NR₁₂COR₁₃ wherein R₁₂ is selected from hydrogen or alkyl and R₁₃ is selected from hydrogen, alkyl, substituted alkyl, C₁₋₃alkoxyl, carboxyalkyl, R₃₀R₃₁N(CH₂)_(p)—, R₃₀R₃₁NCO(CH₂)_(p)—, aryl, arylalkyl, heteroaryl and heterocyclyl or R₁₂ and R₁₃ taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R₃₀ and R₃₁ are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6, (d) R₄ is selected from the group consisting of (i) hydrogen, (ii) C₁₋₃ straight or branched chain alkyl, (iii) benzyl and (iv) —NR₁₃R₁₄, wherein R₁₃ and R₁₄ are independently selected from hydrogen and C₁₋₆ alkyl;  wherein the C₁₋₃alkyl and benzyl groups are optionally substituted with one or more groups selected from C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈ alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈ carboxylate, amino, NR₁₃R₁₄, aryl and heteroaryl; and (e) X is selected from S and O; with the proviso that when R₄ is isopropyl, then R₃ is not halogen, and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.
 2. The compound of claim 1, wherein R₁ is COOR₆, wherein R₆ is selected from H, optionally substituted C₁₋₈ straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl.
 3. The compound of claim 2, wherein R₆ is selected from H, or C₁₋₈ straight or branched chain alkyl which may be optionally substituted with a substituent selected from CN and hydroxy.
 4. The compound of claim 1, wherein R₂ is selected from optionally substituted aryl and optionally substituted heteroaryl.
 5. The compound of claim 4 wherein the aryl or heteroaryl groups are substituted with one to five members selected from the group consisting of halogen, alkyl, alkoxy, alkoxyphenyl, halo, triflouromethyl, trifluoro or difluoromethoxy, amino, alkylamino, hydroxy, cyano, and nitro.
 6. The compound of claim 4 wherein, R₂ is optionally substituted phenyl or napthyl or R₂ is

optionally substituted, wherein the optional substituents are from one to three members selected from the group consisting of halogen, alkyl, hydroxy, cyano, and nitro.
 7. The compound of claim 1 wherein R₃ is selected from: (i) hydrogen, halo, C₁₋₈ straight or branched chain alkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈ alkylsulfonyl, halogen, nitro, and hydroxy; (ii) —NR₁₀R₁₁ wherein R₁₀ and R₁₁ are independently selected from H, C₁₋₈ straight or branched chain alkyl, arylC₁₋₈alkyl, C₃₋₇ cycloalkyl, carboxyC₁₋₈alkyl, aryl, heteroaryl, and heterocyclyl or R₁₀ and R₁₁ taken together with the nitrogen form a heteroaryl or heterocyclyl group; (iii) —NR₁₂COR₁₃ wherein R₁₂ is selected from hydrogen or alkyl and R₁₃ is selected from hydrogen, alkyl, substituted alkyl, C₁₋₃alkoxyl, carboxyC₁₋₈alkyl, aryl, arylalkyl, R₃₀R₃₁N(CH₂)_(p)—, R₃₀R₃₁NCO(CH₂)_(p)—, heteroaryl and heterocyclyl or R₁₂ and R₁₃ taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R₃₀ and R₃₁ are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6.
 8. The compound of claim 7, wherein R₃ is selected from the group consisting of:


9. The compound of claim 1 wherein R₄ is selected from hydrogen, and C₁₋₃ straight or branched chain alkyl.
 10. The compound of claim 9, wherein R₄ is selected from methyl and amino.
 11. The compound of claim 1 wherein R₁ is COOR₆ and R₂ is selected from the group consisting of substituted phenyl, and substituted naphthyl.
 12. The compound of claim 1 wherein R₁ is COOR₆ where R₆ is alkyl, R₂ is substituted phenyl or naphthyl, and R₃ is selected from the group consisting of H, nitro, amino, NHAc, halo, hydroxy, alkoxy, or a moiety of the formulae:

, alkyl(CO)NH—, and R₄ is selected from hydrogen, C₁₋₃ straight or branched chain alkyl and amino and X is Oxygen.
 13. A compound having the structure:

wherein (a) R₁ is selected from the group consisting of: (i) —COR₅, wherein R₅ is selected from H, optionally substituted C₁₋₈ straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C₁₋₈ alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR₂₀R₂₁ wherein R₂₀ and R₂₁ are independently selected from the group consisting of hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl, benzyl, aryl, or heteroaryl or NR₂₀R₂₁ taken together form a heterocycle or heteroaryl; (ii) COOR₆, wherein R₆ is selected from H, optionally substituted C₁₋₈ straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C₁₋₈ alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR₂₀R₂₁ wherein R₂₀ and R₂₁ are independently selected from the group consisting of hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl, benzyl, aryl, or heteroaryl or NR₂₀R₂₁ taken together form a heterocycle or heteroaryl; (iii) cyano; (iv) a lactone or lactam formed with R₄; (v) —CONR₇R₈ wherein R₇ and R₈ are independently selected from H, C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl,  or R₇ and R₈ taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group; (b) R₂ is —NR₁₅R₁₆ wherein R₁₅ and R₁₆ are independently selected from hydrogen, optionally substituted C₁₋₈ straight or branched chain alkyl, arylalkyl, C₃₋₇ cycloalkyl, aryl, heteroaryl, and heterocyclyl or R₁₅ and R₁₆ taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R₂ is NHR₁₆, R₁ is not —COOR₆ where R₆ is ethyl; (c) R₃ is from one to four groups independently selected from the group consisting of: (i) hydrogen, halo, C₁₋₈ straight or branched chain alkyl, arylalkyl, C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈ alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈ carboxylate, aryl, heteroaryl, and heterocyclyl; (ii) —NR₁₀R₁₁ wherein R₁₀ and R₁₁ are independently selected from H, C₁₋₈ straight or branched chain alkyl, arylalkyl, C₃₋₇ cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R₁₀ and R₁₁ taken together with the nitrogen form a heteroaryl or heterocyclyl group; (iii) —NR₁₂COR₁₃ wherein R₁₂ is selected from hydrogen or alkyl and R₁₃ is selected from hydrogen, alkyl, substituted alkyl, C₁₋₃alkoxyl, carboxyalkyl, R₃₀R₃₁N(CH₂)_(p)—, R₃₀R₃₁NCO(CH₂)_(p)—, aryl, arylalkyl, heteroaryl and heterocyclyl or R₁₂ and R₁₃ taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R₃₀ and R₃₁ are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6, wherein the alkyl group may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl; (d) R₄ is selected from the group consisting of (i) hydrogen, (ii) C₁₋₃ straight or branched chain alkyl, (iii) benzyl and (iv) —NR₁₃R₁₄, wherein R₁₃ and R₁₄ are independently selected from hydrogen and C₁₋₆ alkyl;  wherein the C₁₋₃alkyl and benzyl groups are optionally substituted with one or more groups selected from C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈ alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈ carboxylate, amino, NR₁₃R₁₄, aryl and heteroaryl; and (e) X is selected from S and O; and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.
 14. The compound of claim 13, wherein R₁ is COOR₆ wherein R₆ is alkyl, R₂ is NR₆R₇, and R₃ is selected from the group consisting of

, alkyl(CO)NH—, NH₂, NO₂, halogen, and hydrogen, and R₄ is selected from hydrogen, C₁₋₃ straight or branched chain alkyl and amino and X is Oxygen.
 15. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester.
 16. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-(acetylamino)-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester.
 17. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester.
 18. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-2-methyl-4-(4-methyl-1-naphthalenyl)-5-oxo-, methyl ester.
 19. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-8-nitro-5-oxo-, methyl ester.
 20. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7,8-dichloro-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester.
 21. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-[(3-carboxy-1-oxopropyl)amino]-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester.
 22. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-[(3-carboxy-1-oxopropyl)amino]-2-methyl-4-(4-methyl-1-naphthalenyl)-5-oxo-, methyl ester.
 23. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-8-[[4-(hydroxyamino)-1,4-dioxobutyl]amino]-2-methyl-5-oxo-, methyl ester.
 24. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl)amino]acetyl]amino]-2-methyl-5-oxo-, methyl ester.
 25. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-[(4-carboxy-1-oxobutyl)amino]-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester.
 26. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl)methylamino]acetyl]amino]-2-methyl-5-oxo-, methyl ester.
 27. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-8-[(4-morpholinylacetyl)amino]-5-oxo-, methyl ester.
 28. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-5-oxo-8-[(1-piperazinylacetyl)amino]-, methyl ester.
 29. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 2-amino-4-(1,3-benzodioxol-5-yl)-5-oxo-, ethyl ester.
 30. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(6-bromo-1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester.
 31. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester.
 32. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(6-bromo-1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, methyl ester.
 33. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 2-methyl-4-(3-methylphenyl)-5-oxo-, methyl ester.
 34. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester.
 35. The compound of claim 1, which is 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester.
 36. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
 37. A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable carrier.
 38. A method of treating a subject having a disorder ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the compound of claim 1 or
 13. 39. A method of preventing a disorder ameliorated by reducing PDE activity in appropriate cells in a subject, comprising administering to the subject a prophylactically effective dose of the compound of claim 1 or 13 either preceding or subsequent to an event anticipated to cause a disorder ameliorated by reducing PDE activity in appropriate cells in the subject.
 40. The method of claim 38 or 39 comprising administering to the subject a therapeutically or prophylactically effective dose of pharmaceutical composition of claim 36 or
 37. 41. A method of inhibiting PDE activity in a subject, which comprises contacting one or more T-cells with a therapeutically effective dose of the compound of claim 1 or
 13. 42 The method of claim 38, 39 or 41, wherein the disorder is selected from the group consisting of transplant-related disorders, inflammatory-related disorders, AIDS-related disorders, vascular diseases, and erectile dysfunction.
 43. The method of claim 38, wherein the disorder is selected from the group consisting of hypersensitivity, allergy, arthritis, asthma, bee sting, animal bite, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, a urinary tract disorder, inflammatory bowel disease, stroke, erectile dysfunction, HIV/AIDS, cardiovascular disease, gastrointestinal motility disorder, and psoriasis.
 44. A method of artificially modifying an animal, comprising administering to the animal's T-cells a compound of claim 1 or
 13. 45. A method of claim 44 wherein the animal is a mammal.
 46. A method of claim 45 wherein the animal is selected from the group consisting of mouse, rat, rabbit, and guinea pig.
 47. A method of treating a subject having a disorder ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of a compound having the structure of Formula I wherein R₄ is C₁₋₈ straight or branched chain alkyl and X is O. 